Abstract 1646: IK-930, a paralog-selective TEAD inhibitor for treating YAP/TAZ-TEAD dependent cancers
Authors: Nathan Young, George Punkosdy, Jill Cavanaugh, Collin Bantle, Alex Constan, Bin Li, James Conley, Marta Sanchez-Martin, Lan Xu, Karen McGovern, Alfredo Castro, Michelle Zhang, Jeffrey Ecsedy
Journal: Cancer Research (2023)

Abstract The Hippo signaling cascade regulates cell proliferation and survival, as well as overall tissue homeostasis. These functions are mediated by the TEAD family of transcription factors which, when bound to the co-activators YAP or TAZ, induce expression of pro-growth and anti-apoptotic genes. This pathway is frequently dysregulated across tumor types, with genetic alterations along with other mechanisms driving hyper-active YAP/TAZ-TEAD. In addition, Hippo signaling mediates resistance to therapies targeting key oncogenic pathways such as EGFR and RAS. As a result, TEAD transcription factors are promising therapeutic targets. The TEAD family comprises four paralogs (TEAD1-4) that have both over-lapping and non-redundant functions. Given the essential roles of the Hippo pathway in normal physiology, it may be beneficial to target a subset of TEADs to minimize potential on-target toxicity while maintaining anti-tumor efficacy. Although highly homologous, the lipid-binding pocket of TEADs harbor some sequence divergence, highlighting an opportunity to design paralog-specific compounds. We developed IK-930 as a novel, selective inhibitor that potently blocks TEAD transcriptional activity by disrupting the auto-palmitoylation required for its interaction with YAP/TAZ. To demonstrate the selectivity profile of IK-930, a suite of biochemical assays was employed, all of which showed preferential compound binding to an individual paralog. A novel NanoBRETTM system that enabled quantitative, high-throughput measurements of cellular TEAD engagement also documented selective inhibitor interaction with the same family member. To assess how differences in selectivity affect therapeutic index, the in vivo efficacy and toxicity of IK-930 was compared to a pan-TEAD inhibitor. In several Hippo-mutated xenograft models, both compounds displayed potent anti-tumor activity. Moreover, IK-930 exhibited synergy with targeted agents, including EGFR inhibitors, indicating that its selectivity profile could drive robust efficacy in diverse tumor types. Previous studies in genetically engineered mouse models reported that perturbation of YAP/TAZ results in kidney toxicity. Treatment with a pan-TEAD inhibitor in rats and non-human primates led to substantial proteinuria and kidney pathology at exposures similar to those needed for antitumor activity in mouse models. In contrast, IK-930 demonstrated limited kidney toxicity in rats above efficacious doses and no signs of renal problems in non-human primates. Collectively, these results suggest that paralog selectivity with IK-930 broadens the therapeutic window of this novel compound class. With its distinct TEAD inhibitory profile, IK-930 offers unique therapeutic index advantages, further supporting its development as a first-in-class paralog-selective TEAD inhibitor. Citation Format: Nathan Young, George Punkosdy, Jill Cavanaugh, Collin Bantle, Alex Constan, Bin Li, James Conley, Marta Sanchez-Martin, Lan Xu, Karen McGovern, Alfredo Castro, Michelle Zhang, Jeffrey Ecsedy. IK-930, a paralog-selective TEAD inhibitor for treating YAP/TAZ-TEAD dependent cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1646.